ABSTRACT Stuttering is a developmental speech disorder that has one of the highest familial recurrence rates among communication disorders with complex inheritance. While worldwide population prevalence of persistent developmental stuttering is 1%, and 5-6% of children stutter developmentally, an increased prevalence of stuttering (11-14%) has been reported in children in Australia. Genes associated with risk of the disorder have yet to be identified in the non-consanguineous general population; few studies have been conducted on the genetic susceptibility of developmental stuttering, each focusing on families from genetic isolates with high levels of consanguinity. Large-scale, well-powered, population-based studies have not yet been undertaken to detect genomic variants associated with stuttering risk, and as a result extremely little is known about the molecular underpinnings of developmental stuttering. To address this gap in knowledge we propose the follow specific aims. Aim 1) We will build on our existing research program by collecting an additional 2,000 saliva samples from participants diagnosed with developmental stuttering who receive treatment from globally recognized stuttering centers located in England, Australia, Ireland, and the USA. We will also collect through an innovative social media recruitment campaign bringing our total sample of developmental stuttering cases to 3,000. All participants will have diagnoses confirmed by specialists trained in speech and language pathology, dense phenotypic data recorded detailing severity and case history of developmental stuttering, and will be included in genetic analyses utilizing two primary approaches. Aim 2) First, Multi-Ethnic Genotyping Arrays (MEGA) will capture over 2 million variants, providing a genome-wide backbone that will be imputed to the latest whole genome reference panel in all samples, allowing for robust tests of common variant association genome-wide, and second, Aim 3) whole exome sequencing will be performed to selectively capture variation within all protein-coding genes, providing an ideal portrait of the genic regions that are disproportionately burdened with rare and functional variation. A minimum of 5,000 population-based ancestry- matched controls with no known history of speech and language impairment will be selected from Vanderbilt University's BioVU DNA databank as well as the Atherosclerosis Risk in Communities (ARIC) Study. Joint recalling and analysis using these control datasets will power our comprehensive genetic analyses of recovered and persistent developmental stuttering, generating an extremely rich, public resource of results for future genetic, functional, and translational studies. Aim 4) We will identify an additional 1,000 developmental speech disorder cases and 1,000 ancestry-matched controls via electronic medical records in BioVU for replication of top findings. Together, these complementary approaches will lead to identification and validation of genes and pathways contributing to risk of developmental stuttering, providing significant insight into a very common, highly heritable, and often debilitating disorder that today has a largely unknown biological etiology.